This invention is directed to proteinase (protease) inhibitors, and more particularly to N-hydroxy sulfonyl butanamide (hydroxamic acid) compounds that, inter alia, inhibit the activity of matrix metalloproteinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, processes for the preparation of the compounds and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.
Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals make up, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason is involved in a number of disease states. Inhibition of the enzymes responsible for a loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases, or MMPs).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimer""s Disease; multiple sclerosis; coronary thrombosis and bone disease. Defective injury repair processes can also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-xcex1, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-xcex1 convertase is a metalloproteinase involved in the formation of active TNF-U. Inhibition of TNF-xcex1 convertase inhibits production of active TNF-xcex1. Compounds that inhibit both MMPs activity have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There remains a need for effective MMP and TNF-xcex1 convertase inhibiting agents. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-Amyloid Precursor Protein) to the amyloid plaque and inactivation of xcex11-protease inhibitor (xcex11-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as xcex11-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin (MMP-3), gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation in inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
In view of the importance of hydroxamate MMP inhibitor compounds in the treatment of several diseases-and the lack of enzyme specificity exhibited by two of the more potent drugs now in clinical trials, it would be a great benefit if hydroxamates of greater enzyme specificity could be found. This would be particularly the case if the hydroxamate inhibitors exhibited strong inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 that are associated with several pathological conditions, while at the same time exhibiting limited inhibition of MMP-1, an enzyme that is relatively ubiquitous and as yet not associated with any pathological condition. The disclosure that follows describes one family of hydroxamate MMP inhibitors that exhibit those desirable activities
The present invention is directed to a family of molecules that among other properties inhibit matrix metalloprotease (MMP) activity, and particularly inhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, while generally exhibiting little activity against MMP-1. The present invention is also directed to processes for preparing a contemplated compound and for treating a mammal having a condition associated with pathological matrix metalloprotease activity.
Briefly, one embodiment of the present invention is directed to a N-hydroxy sulfonyl butanamide (hydroxamic acid) compound that can act as a matrix metalloprotease enzyme inhibitor. That compound corresponds in structure to Formula I. 
wherein
R1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about the length of a fully extended hexyl group and less than about the length of a fully extended eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is equivalent to about that of one furanyl ring to about that of two phenyl rings;
R2 and R3 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfdonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl, but only one of R2 and R3 is other than hydrido or C1-C4 hydrocarbyl; or
R2 and R3 together with the depicted carbon atom to which they are bonded form a heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen; and
R6 and R7 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfdonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl, but only one of R6 and R7 is other than hydrido or C1-C4 hydrocarbyl; or
R6 and R7 together with the depicted carbon atom to which they are bonded form a heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
only one of R2, R3, R6 and R7 is other than hydrido, C1-C4 hydrocarbyl or forms part of a heterocyclic ring structure as recited.
In preferred embodiments,R2 is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C1-C4 hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl and xe2x80x94Yxe2x80x94Z group, wherein xe2x80x94Y is xe2x80x94O or xe2x80x94NR11, wherein R11 is hydrido or C1-C4 hydrocarbyl, and xe2x80x94Z is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl or (4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C1-C4 hydrocarbylamino)ethyl, 2-[N,N-di(C1-C4 hydrocarbyl)amino]ethyl, carboxy C1-C4 hydrocarbyl, piperidinyl, 2-, 3-, or 4-pyridinyl, sulfonamido, C1-C4 hydrocarbylsulfonyl, C1-C4 hydrocarbylphosphonyl and C(O)xe2x80x94W wherein xe2x80x94W is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy xe2x80x94CHR12NH2 wherein R12 is the side chain of a D or L amino acid, benzyloxy, benzylamino and amino group, or R2 and R3 together form a heterocyclic ring, and R6 and R7 are both either hydrido or methyl. In one of those embodiments, a contemplated compound corresponds in structure Formula II: 
wherein
Ph is a phenyl radical bonded directly to the depicted SO2-group that is itself substituted at its own 4-position with a substituent R4 selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C3-C14 hydrocarbyl group, a C2-C14 hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group;
R2 is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C1-C4 hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl and xe2x80x94Yxe2x80x94Z group, wherein xe2x80x94Y is xe2x80x94O or xe2x80x94NR11, wherein R11 is hydrido or C1-C4 hydrocarbyl, and xe2x80x94Z is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl or (4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C1-C4 hydrocarbylamino)ethyl, 2-[N,N-di(C1-C4 hydrocarbyl)amino]ethyl, carboxy C1-C4 hydrocarbyl, piperidinyl, 2-, 3-, or 4-pyridinyl, sulfonamido, C1-C4 hydrocarbylsulfonyl, C1-C4 hydrocarbylphosphonyl and C(O)xe2x80x94W wherein xe2x80x94W is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy xe2x80x94CHR12NH2 wherein R12 is the side chain of a D or L amino acid, benzyloxy, benzylamino and amino group;
R3 is a hydrido or C1-C4 hydrocarbyl group; or
R2 and R3 together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of repeated administrations is particularly contemplated.
Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, and the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly MMP-13 and/or MMP-2, associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer""s Disease, coronary thrombosis, multiple sclerosis and bone disease.
An advantage of the invention is the provision of a method for preparing such compositions. Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
Another advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-13 and MMP-2 associated with such conditions with minimal side effects resulting from inhibition of other proteinases such as MMP-1, whose activity is necessary or desirable for normal body function.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
In accordance with the present invention, it has been found that certain N-hydroxy sulfonyl butanamide (hydroxamic acid) compounds, also referred to herein as sulfonyl butanhydroxamate compounds, are effective, inter alia, for inhibition of matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain sulfonyl butanhydroxamate compounds are effective for inhibition of collagenase III (MMP-13) and also gelatinase A (MMP-2), which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
Moreover, it has been discovered that many of these sulfonyl butanhydroxamate compounds are selective in the inhibition of MMPs associated with diseased conditions without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that particularly preferred the sulfonyl butanhydroxamate compounds are particularly active in inhibiting of MMP-13 and/or MMP-2, while having a limited or minimal effect on MMP-1. This point is discussed in detail hereinafter and is illustrated in the Inhibition Table hereinafter.
One embodiment of the present invention is directed to a sulfonyl butanhydroxamate compound that can act as a matrix metalloprotease enzyme inhibitor. That compound corresponds in structure to Formula I 
wherein
R1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length that is equivalent to a length that is greater than about that of a fully extended hexyl group and less than about that of a fully extended eicosyl group. In addition, R1 defines a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is equivalent to about that of one furanyl ring to about that of two phenyl rings;
R2 and R3 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfdonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl, but only one of R2 and R3 is other than hydrido or C1-C4 hydrocarbyl; or
R2 and R3 together with the depicted carbon atom to which they are bonded form a heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen; and
R6 and R7 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfdonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl, but only one of R6 and R7 is other than hydrido or C1-C4 hydrocarbyl; or
R6 and R7 together with the depicted carbon atom to which they are bonded form a heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
only one of R2, R3, R6 and R7 is other than hydrido, C1-C4 hydrocarbyl or forms part of a heterocyclic ring structure as recited.
As noted above, an R1 substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group. An R1 substituent also has length, width and substitution requirements that are discussed in detail below. It is noted here, however, that a single-ringed or fused ring cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itself long enough to fulfill the length requirement. As such, that cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself be substituted.
Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals that can constitute a portion of a R1 substituent and are themselves substituted as discussed herein include phenyl, 2-, 3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or 3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or 3-pyrazolidinyl and the like. A phenyl radical is particularly preferred and is used illustratively herein.
When examined along its longest chain of atoms, an R1 substituent, including its own substituent when present, has a total length equivalent to a length that is greater than that of a fully extended saturated chain of six carbon atoms (a hexyl group); i.e., a length of a fully extended heptyl chain or longer, and a length that is less than that of a fully extended saturated chain of about 20 carbons (an eicosyl group). Preferably, that length is equivalent to a length of a fully extended saturated chain of about 8 to about 18 carbon atoms, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
Looked at more generally, and aside from specific moieties from which it is constructed, an R1 substituent (radical, group or moiety) has a length equivalent to that of a fully extended heptyl group or greater. Such an R1 substituent also has a length that is less than that of a fully extended eicosyl group. That is to say that a R1 is a substituent having a length greater than that of a saturated six carbon chain and shorter than that of a saturated twenty carbon chain, and more preferably, a length greater than that of a octyl group and less than that of a palmityl group. The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms of a ring where necessary. Each atom in the chain, e.g. carbon, oxygen or nitrogen, is presumed to be carbon for ease in calculation.
Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by presuming, as is done here, that all atoms have bond lengths of saturated carbon, that unsaturated and aromatic bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a 4-phenyl or 4-pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using a contemplated measurement mode.
In addition, an R1 substituent, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or the SO2-bonded 1-position and through the 3,4 bond of a 5-membered ring radical defines a three-dimensional volume whose widest dimension has the width equivalent to that of about one furanyl ring to about the width of two phenyl rings in a direction transverse to that axis to rotation.
When utilizing this width or volume criterion, a fused ring system such as a naphthyl or purinyl radical is considered to be a 6- or 5-membered ring that is substituted at appropriate positions numbered from the SO2-linkage that is deemed to be at the 1-position as discussed before. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R1 radical as to width when examined using the above rotational width criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too large upon rotation and is excluded.
As a consequence of these length and width requirements, R1 substituents such as 4-(phenyl)phenyl [biphenyl], 4-(4xe2x80x2-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(phenylazo)phenyl 4-(phenylureido)phenyl, 4-(anilino)phenyl, 4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl, 4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularly preferred R1 substituents, with 4-(phenoxy)phenyl and 4-(thiophenyl)phenyl being most preferred.
An SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5- or 6-membered single-ring that is itself substituted with one other substituent, R4. The SO2-linked single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is R4-substituted at its own 4-position when a 6-membered ring and at its own 3-position when a 5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R4 is bonded is preferably a phenyl group, so that R1 is preferably PhR4 in which R4 is bonded at the 4-position of the SO2-linked phenyl (Ph) radical, and in which R4 can itself be optionally substituted as is discussed hereinafter. Substitution at the 2-position of a SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl .radical appears to greatly lessen inhibitory potency toward MMP enzymes, and is absent from a contemplated compound.
A contemplated R4 substituent can be a single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms such as a hydrocarbyl or hydrocarbyloxy group [e.g., C3-C14 hydrocarbyl or O-C2-C14 hydrocarbyl], a phenyl group, a phenoxy group [xe2x80x94OC6H5], a thiophenoxy group [phenylsulfanyl; xe2x80x94SC6H5], an anilino group [xe2x80x94NHC6H5], a phenylazo group [xe2x80x94N2C6H5], a phenylureido group [aniline carbonylamino; xe2x80x94NHC(O)NHxe2x80x94C6H5], a benzamido group [xe2x80x94NHC(O)C6H5], a nicotinamido group [3-NHC(O)C5H4N], an isonicotinamido group [4-NHC(O)C5H4N], or a picolinamido group [2-NHC(O)C5H4N]. As noted before in conjunction with the discussion of R1, most preferred R4 substituents are phenoxy and thiophenoxy groups that are preferably themselves free of substitution. Additionally contemplated R4 substituent groups include a heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and a heteroarylthio group.
A contemplated R4 substituent can itself also be substituted with one or more substituent radicals at the meta- or para-position or both of a six-membered ring with a single atom or a substituent containing a longest chain of up to ten atoms, excluding hydrogen. Exemplary substituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.
Thus, initial studies indicate that so long as the length, substitution and width (volume upon rotation) requirements of an SO2-linked R1 substituent discussed herein are met, an R1 substituent can be extremely varied.
A particularly preferred R4 substituent of an SO2-linked Ph group is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino or benzamido group that is unsubstituted or is itself substituted (optionally substituted) at the para-position when a 6-membered ring or the 3-position when a 5-membered ring. Here, single atoms such as halogen moieties or substituents that contain one to a chain of about ten atoms other than hydrogen such as C1-C10 hydrocarbyl, C1-C9 hydrocarbyloxy or carboxyethyl groups can be used.
Exemplary particularly preferred substituted PhR4 (particularly preferred substituted R1) substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-phenylureido, 4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido. Exemplary particularly preferred R4 groups contain a 6-membered aromatic ring and include a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, a phenylureido group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
More specifically, a particularly preferred sulfonyl butanhydroxamate compounds has an R4 substituent that is a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, a phenylureido group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group or a benzamido group that is itself optionally substituted at its own meta or para-position or both with a moiety that is selected from the group consisting of a halogen, a C1-C9 hydrocarbyloxy (xe2x80x94Oxe2x80x94C1-C9 hydrocarbyl) group, a C1-C10 hydrocarbyl group, a di-C1-C9 hydrocarbylamino [xe2x80x94N(C1-C9 hydrocarbyl)(C1-C9 hydrocarbyl)] group, a carboxyl C1-C8 hydrocarbyl (C1-C8 hydrocarbyl-CO2H) group, a C1-C4 hydrocarbyloxy carbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl-Oxe2x80x94(CO)xe2x80x94C1-C4 hydrocarbyl] group, a C1-C4 hydrocarbyloxycarbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl(CO)xe2x80x94Oxe2x80x94C1-C4 hydrocarbyl] group and a C1-C8 hydrocarbyl carboxamido [xe2x80x94NH(CO)-C1-C8 hydrocarbyl] group, or is substituted at the meta- and para-positions by two methyl groups or by a C1-C2 alkylenedioxy group such as a methylenedioxy group.
Inasmuch as a contemplated SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is itself preferably substituted with a 6-membered aromatic ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R4 substituent is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
Thus, the 1-position of an above-discussed SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is the position at which the SO2-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
R2 and R3 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl. However, only one of R2 and R3 is other than hydrido or C1-C4 hydrocarbyl, with hydrido being the preferred substituent.
Alternatively, R2 and R3 together with the depicted carbon atom to which they are bonded form a heterocyclic ring, preferably a six-membered ring, in which the heteroatom is oxygen, sulfur or nitrogen. That heteroatom is optionally substituted with one or two oxygens when sulfur and is substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen.
R6 and R7 are independently selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, heteroaryl-C1-C4 hydrocarbyl, aryl-C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy-C1-C4 hydrocarbyl, aryloxy-C1-C4 hydrocarbyl, amino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylthio-C1-C4 hydrocarbyl, C1-C4 hydrocarbylsulfdonyl-C1-C4 hydrocarbyl, aminosulfonylamino-C1-C4 hydrocarbyl, aminocarbonylamino-C1-C4 hydrocarbyl, C1-C4 hydrocarbylcarbonylamino-C1-C4 hydrocarbyl and benzyloxy-C1-C4 hydrocarbyl. Again, only one of R6 and R7 is other than hydrido or C1-C4 hydrocarbyl, with both substituents preferably being either hydrido or methyl.
Alternatively, R6 and R7 together with the depicted carbon atom to which they are bonded form a heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen. That heteroatom is optionally substituted with one or two oxygens when sulfur and is substituted with a moiety R5 that is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen.
Preferred R6 and R7 substituents and heterocyclic rings are the same as those noted above for R2 and R3, and therefore will not be repeated here.
It is to be noted that only one of R2, R3, R6 and R7 is other than hydrido, C1-C4 hydrocarbyl or forms part of a heterocyclic ring structure as recited. Thus, the presence of two substituents on two adjacent carbon atoms other than hydrido or C1-C4 hydrocarbyl is not contemplated, nor is the presence of two heterocyclic rings on adjacent carbons.
In preferred embodiments, R6 and R7 are preferably both either hydrido or methyl.
In one particularly preferred embodiment, a contemplated compound corresponds in structure to Formula II, wherein preferred R2 and R3 substituents are as defined below, and R1 is PhR4 wherein Ph is phenyl substituted at the 4-position with substituent R4 that is defined hereinabove. It is noted that preferred R2 and R3 substituents need not be present only when R1 is PhR4, and can be present with any R1 substituent. 
In preferred embodiments, an R2 substituent is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C1-C4 hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl and a xe2x80x94Yxe2x80x94Z group, wherein xe2x80x94Y is xe2x80x94O or xe2x80x94NR11, R11 is hydrido or C1-C4 hydrocarbyl, and xe2x80x94Z is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl or (4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C1-C4 hydrocarbylamino)ethyl, 2-[N,N-di(C1-C4 hydrocarbyl)amino]ethyl, carboxy C1-C4 hydrocarbyl, piperidinyl, 2-, 3-, or 4-pyridinyl, sulfonamido, C1-C4 hydrocarbylsulfonyl, C1-C4 hydrocarbylphosphonyl and C(O)xe2x80x94W wherein xe2x80x94W is selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy xe2x80x94CHR12NH2 wherein R12 is the side chain of a D or L amino acid, benzyloxy, benzylamino and amino group. Thus, where xe2x80x94Y is xe2x80x94O and xe2x80x94Z is hydrido, R2 (xe2x80x94Yxe2x80x94Z) is hydroxyl. Similarly, where xe2x80x94Y is NH and xe2x80x94Z is hydrido, R2 is amino (xe2x80x94NH2).
Exemplary amino acid side chains are those of the naturally occurring L amino acids that can be present in D or L configuration or a mixture thereof. The side chains of the so-called modified and unusual amino acids listed in 37 C.F.R xc2xa7 1.822 are also contemplated here, and those side chains can be present in a D or L configuration or as a mixture.
Preferably, R3 is a hydrido or C1-C4 hydrocarbyl group. More preferably, R3 is hydrido.
Alternatively, R2 and R3 together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen. That heteroatom can be optionally substituted with one or two oxygens when sulfur and can be optionally substituted with a moiety, R5, selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentenyl and cyclohexenyl, C1-C4 carbonylhydrocarbyl such as formyl, acetyl, acryloyl, and butyryl, and sulfonyl C1-C4 hydrocarbyl group such as methylsulfonyl, ethylsulfonyl and the like when nitrogen. Thus, R2 and R3 together with their jointly-bonded carbon atom can form a 4-tetrahydrothiopyranyl group, its corresponding sulfoxide or sulfone, a 4-piperidinyl or a 4-tetrahydropyranyl group. When present, the 4-piperidinyl group can be N-substituted with an above-described R5 substituent.
When R3 is hydrido,as is more preferred, particularly preferred R2 groups include amino, hydroxyl, 2-, 3- and 4-pyridylmethyl, N-pyrrolidinylmethyl and N-piperidinyl. Where R2 and R3 together with their jointly-bonded carbon atom form a six-membered heterocyclic ring, that heteroatom is preferably nitrogen that is optionally substituted as discussed before.
The length of an R1 substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. Thus, a compound having an R1 substituent that is shorter in length than a heptyl group, e.g., a 4-methoxyphenyl group (compound of Example 6), typically exhibits moderate to poor inhibitory activity against all of the MMP enzymes, whereas compounds whose R1 substituents have a length of about an heptyl chain or longer, e.g., a 4-phenoxyphenyl group (compound of Example 5) that has a length of about a nine-carbon chain, typically exhibit good to excellent potencies against MMP-13 or MMP-2 and also selectivity against MMP-1. Exemplary data are provided in the Inhibition Table hereinafter in which the activities of the above two compounds can be compared.
The data of that Table also illustrate that compounds having an R3 group that is hydrido and a nitrogen-containing R2 substituent are particularly effective inhibitors of the activity of MMP-2, while maintaining minimal activity against MMP-1.
In view of the above-discussed preferences, compounds corresponding in structure to particular formulas constitute particularly preferred embodiments.
In one of those embodiments, a contemplated compound corresponds in structure to Formula II, below, wherein preferred R2, R3 substituents and PhR4 are as defined above. 
A compound of Formula II is preferably present in the stereoconfiguration of Formula IIA, below 
In yet another group of preferred compounds, R2 and R3 together with the carbon atom to which they are bonded form a six-membered heterocyclic ring whose heteroatom, X, is O, S, S(O), S(O2) or NR5, e.g., a 4-piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl group. The nitrogen of the 4-piperidinyl group is substituted with a moiety R5 selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and a sulfonyl C1-C4 hydrocarbyl group. The R6 and R7 substituents here are both a hydrido or C1-C4 hydrocarbyl group, preferably methyl. Those preferred compounds correspond in structure generally and specifically to Formulas III and IV, respectively 
Following the preference that each of R6 and R7 be methyl, and the preference that R1 be PhR4, which in turn is phenpoxyphenyl or 4-thiophenoxyphenyl, another particularly preferred compound corresponds in structure to Formula V,below 
The preferred stereoconfiguration of a compound of Formula V is illustrated in Formula VA, below 
Taking in to consideration the further preference that R3 be a hydrido group, a presently most preferred compound corresponds in stereoconfiguration to Formula VI, below 
In another of those embodiments in which the preference for R6 and R7 both being hydrido, a contemplated compound corresponds in structure to Formula VII, below, wherein R2, R3 and PhR4 are as defined above. 
A above compound of this embodiment preferably has the stereoconfiguration shown in Formula VIIA, below 
In a further group of preferred compounds of this embodiment, R2 and R3 together with the carbon atom to which they are bonded form a six-membered heterocyclic ring whose heteroatom, X, is O, S, S(O), S(O2) or NR5, e.g., a 4-piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl group. The nitrogen atom of the 4-piperidinyl group is substituted with a moiety R5 selected from the group consisting of a hydrido, C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 carbonylhydrocarbyl, and a sulfonyl C1-C4 hydrocarbyl group. Those preferred compounds correspond in structure generally and specifically to Formulas VIII and IX, respectively, below 
The word xe2x80x9chydrocarbylxe2x80x9d is used herein as a short hand term to include straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups or radicals, as discussed hereinafter. Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., C1-C4 alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbon atoms, and preferably one to about 10 carbon atoms.
A particularly preferred hydrocarbyl group is an alkyl group. As a consequence, a generalized, but more preferred substituent can be recited by replacing the descriptor xe2x80x9chydrocarbylxe2x80x9d with xe2x80x9calkylxe2x80x9d in any of the substituent groups enumerated herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
Usual chemical suffix nomenclature is followed when using the word xe2x80x9chydrocarbylxe2x80x9d except that the usual practice of removing the terminal xe2x80x9cylxe2x80x9d and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents. Thus, a hydrocarbyl ether is referred to as a xe2x80x9chydrocarbyloxyxe2x80x9d group rather than a xe2x80x9chydrocarboxyxe2x80x9d group as may possibly be more proper when following the usual rules of chemical nomenclature. On the other hand, a hydrocarbyl group containing a carbonyl group is referred to as a hydrocarboyl group inasmuch as there is no ambiguity in using that suffix. As a skilled worker will understand, a substituent that cannot exist such as a C1 alkenyl group is not intended to be encompassed by the word xe2x80x9chydrocarbylxe2x80x9d.
The term xe2x80x9ccarbonylxe2x80x9d, alone or in combination, means a xe2x80x94C(xe2x95x90O)xe2x80x94 group wherein the remaining two bonds (valences) are independently substituted. The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d, alone or in combination, means a xe2x80x94SH group. The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, means an amine or xe2x80x94NH2 group, whereas the term mono-substituted amino, alone or in combination, means a substituted amine xe2x80x94N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a xe2x80x94N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups. Amines, amino groups and amides are classes that can be designated as primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) or unsubstituted, mono-substituted or di-substituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (IVxc2x0) means a nitrogen with four substituents (xe2x80x94N+ (substituent)4) that is positively charged and accompanied by a counter ion or N-oxide means one substituent is oxygen and the group is represented as (xe2x80x94N+ (substituent)3xe2x80x94O31); i.e., the charges are internally compensated.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, means a xe2x80x94C-triple bond-N (xe2x80x94CN) group. The term xe2x80x9cazidoxe2x80x9d, alone or in combination, means a xe2x80x94N-double bond-N-double bond-Nxe2x80x94 (xe2x80x94Nxe2x95x90Nxe2x95x90Nxe2x80x94) group.
The term xe2x80x9chydroxylxe2x80x9d, alone or in combination, means a xe2x80x94OH group. The term xe2x80x9cnitroxe2x80x9d, alone or in combination, means a xe2x80x94NO2 group.
The term xe2x80x9cazoxe2x80x9d, alone or in combination, means a xe2x80x94Nxe2x95x90Nxe2x80x94 group wherein the bonds at the terminal positions are independently substituted. The term xe2x80x9chydrazinoxe2x80x9d, alone or in combination, means a xe2x80x94NH-NHxe2x80x94 group wherein the remaining two bonds (valences) are independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d, alone or in combination, means a xe2x80x94S(O)2xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfoxidoxe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)1xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfonylamidexe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)2xe2x80x94Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted. The term xe2x80x9csulfinamidoxe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)1Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted. The term xe2x80x9csulfenamidexe2x80x9d, alone or in combination, means a xe2x80x94Sxe2x80x94Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted.
The term xe2x80x9chydrocarbyloxyxe2x80x9d, alone or in combination, means an hydrocarbyl ether radical wherein the term hydrocarbyl is as defined above. Examples of suitable hydrocarbyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term xe2x80x9ccyclohydrocarbylxe2x80x9d, alone or in combination, means a hydrocarbyl radical that contains 3 to about 8 carbon atoms, preferably from about 3 to about 6 carbon atoms, and is cyclic. The term xe2x80x9ccyclohydrocarbylhydrocarbylxe2x80x9d means an hydrocarbyl radical as defined above which is substituted by a cyclohydrocarbyl as also defined above. Examples of such cyclohydrocarbylhydrocarbyl radicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl cyclooctynyl and the like.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical that optionally carries one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term xe2x80x9carylhydrocarbylxe2x80x9d, alone or in combination, means an hydrocarbyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like. The term xe2x80x9carylhydrocarbyloxycarbonylxe2x80x9d, alone or in combination, means a radical of the formula xe2x80x94C(O)xe2x80x94Oxe2x80x94 arylhydrocarbyl in which the term xe2x80x9carylhydrocarbylxe2x80x9d has the significance given above. An example of an arylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term xe2x80x9caryloxyxe2x80x9d means a radical of the formula aryl-Oxe2x80x94 in which the term aryl has the significance given above. The term xe2x80x9caromatic ringxe2x80x9d in combinations such as substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfinamide or substituted-aromatic ring sulfenamide means aryl or heteroaryl as defined above.
The terms xe2x80x9chydrocarbyloylxe2x80x9d or xe2x80x9chydrocarbylcarbonylxe2x80x9d, alone or in combination, mean an acyl radical derived from an hydrocarbylcarboxylic acid, examples of which include acetyl, propionyl, acryloyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term xe2x80x9ccyclohydrocarbylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionally substituted by, for example, a hydrocarbyloylamino group, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms xe2x80x9carylhydrocarbyloylxe2x80x9d or xe2x80x9carylhydrocarbylcarbonylxe2x80x9d mean an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid such as phenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl, 4-methoxycinnamoyl and the like.
The terms xe2x80x9caroylxe2x80x9d or xe2x80x9carylcarbonylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one to four hetero atoms selected from nitrogen, oxygen and sulphur, which is optionally substituted on one or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by an hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl or arylhydrocarbyl or on a tertiary nitrogen atom (i.e. xe2x95x90Nxe2x80x94) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also form a N-oxide [xe2x95x90N(O)xe2x80x94] group. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or a heteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocycle that contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl. A xe2x80x9cheteroarylxe2x80x9d group is an aromatic heterocyclic ring substituent that can contain one, two, three or four atoms in the ring that are other than carbon. Those heteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single five- or 6-membered ring or a fused ring system that contains two 6-membered rings or a five- and a 6-membered ring. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups ; six/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups ; and six/6-membered fused rings such as 1,2-,.1,4-,.2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.
The term xe2x80x9ccyclohydrocarbylhydrocarbyloxy-carbonylxe2x80x9d means an acyl group derived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-Oxe2x80x94COOH wherein cyclohydrocarbylhydrocarbylhas the significance given above. The term xe2x80x9caryloxyhydrocarbyloylxe2x80x9d means an acyl radical of the formula aryl-Oxe2x80x94hydrocarbyloyl wherein aryl and hydrocarbyloyl have the significance given above. The term xe2x80x9cheterocyclyloxycarbonylxe2x80x9d means an acyl group derived from heterocyclyl-Oxe2x80x94COOH wherein heterocyclyl is as defined above. The term xe2x80x9cheterocyclylhydrocarbyloylxe2x80x9d is an acyl radical derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid wherein heterocyclyl has the significance given above. The term xe2x80x9cheterocyclylhydrocarbyloxycarbonylxe2x80x9d means an acyl radical derived from a heterocyclyl-substituted hydrocarbyl-Oxe2x80x94COOH wherein heterocyclyl has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical derived from a carboxylic acid represented by heteroaryl-Oxe2x80x94COOH wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like. The term xe2x80x9caminohydrocarbyloylxe2x80x9d means an acyl group derived from an amino-substituted hydrocarbylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. The term xe2x80x9chalohydrocarbylxe2x80x9d means a hydrocarbyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such halohydrocarbyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term perfluorohydrocarbyl means a hydrocarbyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluorohydrocarbyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
Table 1 through Table 37, below, show several contemplated N-hydroxy sulfonyl butanamide compounds as structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1, are as shown in each Table. One bond (straight line) is shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations.
Compounds of the invention can be produced in accordance with the following generic synthetic Schemes A-D. It is noted that the numbers shown on R groups these schemes, except in Scheme D, are different from those utilized in structural formulas having Roman numerals. That difference in numbering is to illustrate the generality of these synthesis schemes. Specific synthetic schemes that illustrate the preparation of specific compounds follow hereinafter. 
The above syntheses, as with all of the reactions discussed herein, can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolyses, can be carried out under laboratory air.
The compounds of this invention are described above. This description includes 4-sulfonehydroxamates and hydroxamate derivatives as defined wherein 4 refers to the position of the sulfonyl group removed from the carbonyl group of the hydroxamic acid group. The placement of that sulfur can also shown by using the terms alpha ( ), beta ( ), gamma ( ) or omega ( ) wherein alpha is the 2-position relative to the carboxyl or carboxyl derivative carbonyl, beta is the 3- position relative to the carboxyl or carboxyl derivative carbonyl, gamma is the 4- position relative to the carboxyl or carboxyl derivative carbonyl and omega is the last position relative to the carboxyl or carboxyl derivative. Omega is a general term that denotes the last position in a chain without regard to the length of the chain.
As non-limiting examples, oxidations, reductions, organometallic additions, hydrolyses, SN2 reactions, conjugate additions, carbonyl additions, aromatic displacements and the like can be included. A person skilled in the art can apply the reactions to these compounds or readily adapt or change synthetic procedures to a specific example as required.
In general, the choices of starting material and reaction conditions can vary as is well know to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required and selected by one skilled in the art. Conditions can also be selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually be minimized. Examples of such less desirable materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.
Various reactions illustrated in the above Schemes can be base mediated by the use of catalytic amounts of some bases or carried out with an equivalent or more of a base by the addition of an additional reagent or the thiol reagent can be a preformed thiol salt such as the sodium salt of a thiophenol. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides.
As non-limiting examples, such amines can include triethyl amine, trimethyl amine, diisopropyl amine, methyldiisopropyl amine, diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine, N-methylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,Nxe2x80x2-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzylmethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N,Nxe2x80x2, Nxe2x80x2,-tetramethylpiperazenium hydroxide, and N-ethyl-Nxe2x80x2-hexylpiperidinium hydroxide and the like.
Metal hydrides, amide or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like may also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadium reagents such as dimethylcadium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents.
The reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making the products of this invention and the like. Room temperature or less or moderate warming (xe2x88x9210xc2x0 C. to 60xc2x0 C.) are the preferred temperatures of the reaction. If desired, the reaction temperature might be about xe2x88x9276xc2x0 C. to the reflux point of the reaction solvent or solvents.
An intermediate thioether can be oxidized to the sulfone in one step using two equivalents to oxidizing agent. Reagents for this process can, in a non-limiting example, include peroxymonosulfate (OXONE(copyright)), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorus acid, sodium meta-peroiodate, periodic acid and the like. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.
The oxidation can be carried out at temperature of about xe2x88x9278xc2x0 to about 50xc2x0 degrees centigrade and normally selected from a range xe2x88x9210xc2x0 C. to about 40xc2x0 C. Preparation of a desired sulfone can be carried out in a two-step process using about one equivalent of oxidizing agent to first form the sulfoxide at about 0xc2x0 C. A second oxidation then pproduces the sulfone.
The solvents listed above can be used with these selective oxidations with, for example, methanol or methanol/water being preferred along with a temperature of from about xe2x88x9210xc2x0 C. to 30xc2x0 C. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents.
A hydroxamate can be prepared from the corresponding ester by reaction of the ester with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents such as those listed above. This exchange process can be further catalyzed by the addition of additional acid.
Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine in situ which can exchange with an ester or amide. The exchange can be carried out with a protected hydroxyl amine such as tetrahydropyranylhydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds in which the ester is a tetrahydropyranyl (THP) or benzyl (Bn) ester.
Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
Oxidizable functional groups are readily recognized by those skilled in the art and alternative synthesis can be used such as the protection/deprotection sequence.
Acids can be converted into activated carbonyl compounds using reagents well know in the art including the peptide and protein synthesis and amino acid coupling or conjugation art. Examples of such reagents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT, isobutylchloroformate an the like. These valuable activated carbonyl intermediates can then be transformed into hydroxamic acids or hydroxamic acid derivatives such as H, benzyl or THP. Preparation of or interconversion between the hydroxylamine or hydroxylamine derivative compounds or acids or amides or esters can be carried out by one skilled in the art using the methods discussed above or by other techniques.
The amine function in the intermediate compounds use a protecting group to facilitate the transformations. Decisions involving the selection of protecting groups and their use can be made by a person skilled in the art. Especially useful are the techniques and reagents used in protein, peptide and amino acid coupling and transformation chemistry. The use of the tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Z) and N,N-dibenzyl groups as will as their synthesis and removal are examples of such protection schemes.
Coupling of the amino acids, amino esters, amino acid hydroxamates or hydroxamate derivatives and amino acid amides of the precursor (intermediate) compounds with, for example, other amino acids, amines, alcohols, amides or acids is also carried out by methods well known in the art such as, for example, active ester or mixed anhydride couplings with preferred bases if required being moderate tertiary amines such as N-methylmorpholine. Removal of a preexisting group that can also serve as a protecting group or blocking group such as the acetyl group and the like is also accomplished using standard hydrolysis conditions such as base hydrolysis or exchange or acid exchange or hydrolysis.
In the case of compounds with an amine group, it is sometimes desirable to use acidic conditions with a reagent such as hydrogen peroxide and/or in combination with an acidic reagent such as periodic acid, peracetic acid and the like. It should also be noted by one skilled in the art that hydrolysis or exchange of the acetyl group may or may not effect hydrolysis or exchange of a ester, amide or hydroxamate function.
Preparation of yet another class of compounds of this invention, those containing the alpha-hydroxy carbonyl function, typically uses the SN2 class of reactions. A bimolecular nucleophilic displacement (SN2) reaction is illustrated in a step wherein a halogen is displaced by a thiol compound or the salt of a thiol compound. The thiol anion can be derived from a preformed salt or the salt can be formed in situ via addition of a base.
Preferred bases are those that are hindered such that competition with thiolate anion in a two stage reaction is minimized. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of a preferred class.
A protecting group P on the alpha-hydroxy group canalso be utilized. Such protecting groups can include acyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups trisubstituted silyl groups and the like. Examples of such protecting groups include acetyl, THP, Benzyl, Z, tert-butyldimethylsilyl (TBDMS) groups. The preparation of such protected alcohols as well as the removal of the protecting groups is well known in the art and its practitioners.
The selection of an atmosphere for the reactions of these Schemes as well as the other Schemes depends, as usual, a number of variables known to those skilled in the art. The choices can be an inert atmosphere such as nitrogen, argon, helium and the like or normal or dry air. Preferred is the use of an inert atmosphere if there is an uncertantity as to the requirements of the process.
One of these variables particularly requiring the attention of the skilled person is control of oxidation by air or another means of a thiol or the salt of a thiol to its corresponding disulfide or mixed disulfide. The used of a damp atmosphere while carrying out an organometallic compound requiring synthesis not desirable for either economic or safety reasons whereas the use of air is normal for aqueous hydrolysis or exchange reactions where oxidation, for example, is not probable.
Addition of an organometallic reagent such as a Grignard Reagent, lithium organometallic reagent, zinc organometallic reagent, cadium organometallic reagent, sodium organometallic reagent or potassium organometallic regent to a carbonyl group such as an aldehyde, ketone, ester, amide (primaryI, secondary, tertiary), acid chloride, anhydride, mixed anhydride, hydroxamate derivative (mono- or bis-), carbonate, carbamate or carbon dioxide is illustrated in the Schemes such as Schemes A, B and C. The products of such reactions of organometallic compounds with carbonyl compounds are well known to those skilled in the art. Well know examples include the preparation of alcohols by reaction with aldehydes, acids by reaction with carbon dioxide and esters by reaction with carbonate esters.
For example, in Scheme A, the product of such a reaction can be an alcohol such as compound 39 or an ester, amide, ketone or aldehyde. It is also recognized by those skilled in the art that the carbonyl compound and the organometallic compound can be exchanged or interchanged or otherwise manipulated to synthesize the same or a similar compound. For example, although not contemplated herein, carbonyl compound 38 in Scheme A wherein R6 is methyl (or ethyl) can be reacted with ethyl magnesium bromide (or methyl magnesium bromide) to form compound 39 where R7 is ethyl (or methyl) and organometallic compound 53 in Scheme B where one of R7 and R6 is methyl one is ethyl can be treated with water to also form compound 39.
An alcohol can also be converted into a halogen or sulfonate ester. Either product, as shown with the sulfides, can be oxidized or, once oxidized, reduced back to a sulfide or sulfoxide. In addition, the alcohol with the sulfur oxidized can also be converted into, for example, its corresponding halogen or sulfonated ester.
The halogen compounds such as those in Schemes A, B and C, for example, with or without the sulfur oxidized can be reacted with a metal to form an organometallic reagent such as those listed above. The organometallic compound can then be reacted with a carbon-oxygen double bond-containing molecule to produce precursors to compounds of this invention including homologous acids, esters, amides (primary, secondary, tertiary), ketones, aldehydes and the like.
If the product of the reaction of an organometallic compound with a carbonyl compound is itself another carbonyl containing compound such as shown, for example, by the synthesis of compounds 64 or 65 in Scheme C, the product can be either a metalloprotease inhibiting product of this invention or an intermediate for the synthesis of a homologous metalloprotease inhibiting compound of this invention. As was discussed above with respect to alcohols and illustrated in these Schemes, these carbonyl products can be oxidized at sulfur before or after further modification.
A lactone ring where R2 through R7 inclusive are as defined above can be opened with a thiolate anion to provide a 4-thia acid (omega-thia acid, gamma-thia acid) or salt. An example of a preferred thiol is 4-phenoxybenzenethiol. The sulfide formed can them be oxidized to the corresponding sulfone, converted to the hydroxamate or protected hydroxamate, deprotected if required all by methods discussed and illustrated above and known in the art.
Alternatively, a Lewis acid in the presence of a thiol can be used to form the thia acid. Opening of the lactone with a Lewis such as zinc bromide or zinc chloride in the presence of thionyl bromide or thionyl chloride can provide an omega-halo acid halide (activated carbonyl). This intermediate derivatives as desired at the carbonyl carbon can be prepared to provide a protected carbonyl compounds such as an ester or an amide or used to form a hydroxamic acid or protected hydroxamic acid directly; i.e., a omega-halo ester, amide, hydroxamic acid or protected hydroxamate.
The 4-chloro or 4-bromo group can be displaced via a nucleophilic substitution reaction (SN2) using a xe2x80x94SR1 reagent to provide a thia-compound that can then be oxidized as outlined above to provide a desired compound. Preferred lactones can include 2-methylbutyrolactone, 2-hydroxy-3,3-dimethylbutyrolactone and 2-piperidylbutyrolactone. Preferred omega-haloesters include, methyl 2,2-dimehyl-4 chlorobutyrate and ethyl 4-bromobutyrate.
Alpha-halolactones can be utilized in the preparation of compounds of this invention wherein the alpha-carbon of the product hydroxamic acids are substituted with a nucleophile such as a hydroxyl, ether, azide or an amine. These intermediates, when stable to the reaction conditions, properly protected or converted in a later step to the desired function can provide substrates for the lactone dependant reactions discussed above. Bromobutyrolactone is a preferred halolactone.
Compounds of this invention can be prepared by alkylation of a carbanion (nucleophile) generated from a protected carboxylic acid using processes known in the art. Protecting groups for the carboxyl function include, for example, esters such as tert-butyl esters. Bases for forming the anion are can be organometallic reagents such as tert-butyl lithium, metal amides such as lithium diisopopyl amide (LDA) or alkoxides such as potassium tert-butoxide. Other candidate bases are discussed above.
Following or during formation of the anion, the alkylating agent (electrophile) is added which undergoes a nucleophilic substitution reaction. Electrophilic substrates for displacement can include, for example, dihalo alkanes such as 1,2-dihaloalkanes or mono-halo-mono sulfated alkanes or bissulfonate alkane esters. 1,2-di-Bromoethanes, 1-chloro-2, bromoethanes, 1-chloro-2-tosylethanes and 1,2-di-toluenesulfonylethanes are examples of such bis-electrophiles. 1-Bromo-2-chloro-ethane is a preferred electrophile.
Activated ester groups are well known in the art and can include, for example, di-easters such as malonates, ester-ketones such as acetoacetic esters or ester-aldehydes that are subject to carbonyl addition reactions. Alkylation with one equivalent of alkyating agent followed by derivatization of the new omega carbonyl group with, for example, an organometallic reagent or reduction to form an alcohol which can then be derivatized to form a carbon halogen bonds or an activated ester such as a sulfate ester. These omega-substituted compounds can serve as substrates for the thioate displacement and oxidation reactions discussed above to form the carboxylic acid compounds or intermediates of this invention.
Omega-haloalcohols can be useful starting materials for the preparation of compounds of this invention using alternative synthetic sequences from those discussed above. They can serve as substrates for R1 thiolate displacement (SN2) to provide 4-sulfides (thio ethers) which can then be oxidized to the desired sulfones. The HS-R1 compounds can be prepared as discussed below and oxidized as discussed above. Preparation of the R1 group can be via an intermediate such as a fluorothiophenol followed by displacement of the fluoride with a second nucleophile to produce compounds or intermediates of this invention. Flourothiophenol and phenol and 2,3-dimethyl phenol are examples of preferred thiols and phenols, respectively. The sulfone alcohols can be oxidized to the corresponding carboxylic acids as well as to the corresponding aldehydes.
The carboxylic acids or protected carboxylic acids can be utilized as presented herein. The aldehydes can serve as useful intermediates for homologation to an alpha-hydroxysulfone acid compound that can serve as a substrate for preparation of a hydroxamic acid or hydroxamate of this invention. Homologation of an aldehyde can be carried out by adding a cyanide to the aldehyde to form a alpha-cyano-omegasulfone (cyanohydrin) which can then be hydrolysed with an acid such as those discussed above to form a alpha-hydroxy carboxylic acid useful in the synthesis of compounds of this invention. Cyanohydrins can be prepared by methods well known in the art such as treatment of an aldehyde with a metal cyanide, hydrogen cyanide or trimethylsilylcyanide. Trimethylsilylcyanide is a preferred reagent.
The preparation of compounds of this invention based on alpha-oxygen-substituted compounds such as the hydroxyl group is discussed and illustrated and the methods are well known in the art. Protection of the alcohols of this invention or of the intermediate alcohols used in this invention is also well known.
The preparation of ethers can be carried out by forming a salt of the alcohol and treating this nucleophile with an electrophile such as a halide or an activated ester such as a sulfate ester. The salt is formed by treating the alcohol with a base such as is discussed above. Examples of such bases are lithium alkyls, metal hydrides or the metal salts of an amine such as LDA.
Halides can be chlorides, bromides or iodides and sulfates can be, for example, benzene sulfonates, tosylates, mesylates or triflates. An example of a preferred electrophile is 2-chloromethylpyridine and a preferred base is sodium hydride. Alternatively, the alcohol can be converted into a leaving group (electrophilic reagent) and then treated with a nucleophile. Examples of such leaving groups include sulfate esters such tosylates, mesylates and triflates whose preparation is discussed above. The triflate is a preferred leaving group.
Displacement of these groups with nucleophiles is well known in the art and discussed and/or illustrated above. The nucleophiles can be hydroxide to allow inversion of stereochemistry, alkoxides to form ethers, amines or ammonia to form substituted amines or an azide anion to form an azide. A preferred nucleophile the is tetra-(n-butyl)ammonium azide. The azido compound, for example, can be reduced to form the amino acid. Reductions are discussed above and are well known in the art. A preferred method is hydrogenation with palladium on carbon catalyst.
The amines, including the amino acids, of this invention can be acylated or alkylated by methods well known in the art. The amides formed can be considered as protected amines or as end products of this invention. Acylation to form such derivatives as tert-butoxycarbonyl and carbobenzyloxy carbonyl group is discussed above. Other acyl (Ac) groups can be, for example, acetyl, haloacetyl, aroyl, substituted aroyl, heteroaroyl, substituted heteroaroyl or other groups as required. The amines can be acylated using anhydrides, mixed anhydrides, acid chlorides or activated esters. Usually such acylations are carried out in presence of a base such as the bases discussed above and well known in the art. Examples are N-methyl-morpholine, triethylamine and the like.
The carboxyl compounds useful herein having amide substituents can be treated, converted or interconverted as shown and/or dicussed above to form the products of this invention. In addition, the haloacetyl compounds such as the preferred 2-chloroacetamide derivative can be treated with an amine as a nucleophile to yield an aminoacid. Again, these reactions are well known in the art. A preferred amine is morpholine.
The cyclic amino acids used to prepare desired compounds can be prepared in ways know to those skilled in the art. Reduction of heteroaryl or unsaturated or partially unsaturated heterocycles can be carried out. For example, the six membered ring compounds can be synthesized by reduction of the corresponding 2-, 3- or 4-pyridine carboxylic acids, 2-, or 3-pyrazole carboxylic acids or derivatives thereof. The reduction can by hydrogenation in the presence of a catalyst or hydride reduction using a hydride transfer agent such as lithium aluminum hydride. The starting amino acids or their derivatives, such as ethyl isonipecotate, ethyl nipecotate, pipecolinic acid, proline or its isomers, pyroglutamate or its isomers are starting materials that can be used to prepared a compound of this invention.
The R, S and RS isomers of the amino acids can be used. Some starting material can be obtained from commercial sources. A preferred starting material is ethyl isonipecotate.
Alkylation of the aminoacid at the carbon alpha to the carbonyl group to form a useful compound can be carried out by first forming an anion using a base. Exemplary bases are discussed elsewhere. The preferred bases are strong bases that are either hindered and/or non-nucleophilic such as lithium amides, metal hydrides or lithium alkyls. A preferred base is lithium diisopropylamide (LDA) in a dipolar aprotic solvent or THF.
Following or during formation of the anion, an alkylating agent (an electrophile) is added which undergoes a nucleophilic substitution reaction. Non-limiting examples of such alkylating agents are 1,2-dihaloalkanes or haloalkanes also substituted by an activated ester group. Activated ester groups are well known in the art and can include, for example, an ester of a 2-halo-alcohol such as a bromo-, iodo- or chloro-ethane para-toluene sulfonate, triflate or mesylate. A preferred alkylating agents is 1-bromo-2-chloroethane.
The nitrogen substituent on the cyclic aminoacid portion of the compounds of this invention can be varied. In addition, this can be accomplished at different stages in the synthetic sequence based on the needs and objectives of the skilled person preparing the compounds of this invention.
The N-side chain variations can include replacing the hydrogen substituent with a alkyl, arylalkyl, alkene or alkyne. This can be accomplished by methods well known in the art such as alkylation of the amine with an electrophile such as halo- or sulfate ester (activated ester) derivative of the desired sidechain. This can be done in the presence of a base such as those discussed above and in a pure or mixed solvent as discussed above. A preferred base is postassium carbonate and a preferred solvent is DMF.
The alkenes and alkynes can be reduced. if desired, by, for example, hydrogenation with a metal catalyst and hydrogen, to an alkyl or arylalkyl compound of this invention and the alkyne or arylalkyne can be reduced to a alkene of alkane with under catalytic hydrogenation conditions as discussed above dor with an deactivated metal catalyst. Catalysts can include, for example, Pd, Pd on Carbon, Pt, PtO2 and the like. Less robust catalysts include such thing as Pd on BaCO3 or Pd with quinoline or/and sulfur.
An alternative method for alkylation of the amine nitrogen is reductive alkylation. This process, well known in the art, allows treatment of the secondary amine with an aldehyde or ketone in the presence of a reducing agent such as borane, borane:THF, borane:pyridine, lithium aluminum hydride. Alternatively, reductive alkylation can be carried out hydrogenation conditions in the presence of a metal catalyst. Catalysts, hydrogen pressures and temperatures are discussed above and are well known in the art. A preferred reductive alkylation catalyst is borane:pyridine complex.
The compounds of this invention include compounds wherein the substituent on nitrogen of the cyclic amino acids as listed above provide amino acid carbamates. Non-limiting examples of these carbamates are the carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl), isobytoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. These materials can be made, as discussed above, at various stages in the synthesis based on the needs and decisions made by a person skilled in the art using methods well know in the art.
Useful synthetic techniques and reagents include those used in protein, peptide and amino acid synthesis, coupling and transformation chemistry. The use of the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) as will as their synthesis and removal are examples of such protection or synthesis schemes discussed above. Transformations of amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives and amino acid amides of this invention or compounds used in this invention can be carried out as discussed and/or illustrated above. This includes, for example, active ester or mixed anhydride couplings wherein preferred bases, if required, are tertiary amines such as N-methylmorpholine.
Reagents for protection of the amine group of the protected amino acids include carbobenzoxy chloride, iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the like which are reacted with the amine in non-protic or dipolar aprotic solvents such as DMF or THF or mixtures of solvents. A preferred reagent is di-tert-butyl dicarbonate and a preferred solvent is THF. Further conversion of the cyclic amino acids of this invention including alkylation, displacement with a thiol or thiolate, oxidation to a sulfone, and conversion into a hydroxamic acid or hydroxamate derivative can be carried out discussed herein.
Sulfone compounds such as those where R1 is nitroaryl can be prepared as compounds of this invention by synthesis of a thiol or thiolate nucleophile, displacement of an electrophile (X) by the nucleophilic thiol or thiolate and oxidation of the product thia ether (sulfide) to the sulfone. For example, displacement of the electrophilic group X with a nitro-benzenethiol can yield a compound where R1 is nitrobenzene that can be reduced to provide a useful amino compound wherein R1 is an aniline. It should be noted that nitrobenzenethiol is an example and not to be considered as limiting or required. Oxidation of the thioether product can be carried out as discussed below when desired.
The reduction of nitro groups to amines is will know in the art with a preferred method being hydrogenation. There is usually a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred. The amino group can be alkylated if desired, or acylated with, for example, an aroyl chloride, heteroaryl chloride or other amine carbonyl forming agent to form an R1 amide.
The amino sulfone or thioether can also be reacted with a carbonic acid ester chloride, a sulfonyl chloride, a carbamoyl chloride or an isocyanate to produce the corresponding carbamate, sulfonamides, or urea. Acylation of amines of this type are well known in the art and the reagents are also well known.
Usually, these reactions are carried out in aprotic solvents under an inert or/and dry atmosphere at about 45xc2x0 C. to about xe2x88x9210xc2x0 C. An equivalent of a non-competitive base is usually used with sulfonyl chloride, acid chloride or carbonyl chloride reagents. Following or before this acylation step, synthesis of the hydroxamic acid products of this invention can proceed as discussed.
Other thiol reagents can also be used in the preparation of compounds of this invention. Examples are fluoroaryl, fluoroheteroaryl, azidoaryl or azidoheteroaryl or heteroaryl thiol reagents. These thiols can be used a nucleophiles to as discused above. Oxidation to the corresponding sulfone can then be carried out. The fluoro substituted sulfone can be treated with a nucleophile such as ammonia, a primary amine, a quaternary ammonium or metal azide salt, under pressure if desired, to provide an azido, amino or substituted amino group that can then be reacted an activated benzoic or substituted benzoic acid derivative to form a benzamide. Azides can be reduced to an amino group using, for example, hydrogen with a metal catalyst or metal chelate catalyst or by an activated hydride transfer reagent. Hydrazo compounds can be oxidized to azo compounds and axo compounds can be reduced to hydrazo compounds. The amines can be acylated as discussed above.
Preferred methods of preparing aminethiol intermediates of this invention include protection of an aromatic or heteroaromatic thiol with trityl chloride to form the trityl thiol derivative, treatment of the amine with as reagent such as an aromatic or heteraromatic acid chloride to form the amide, removal ot the trityl group, with acid to form the thiol. Preferred acylating agents include benzoyl chloride and preferred trityl remoing reagents include triflouroacetic acid and trisiopropylsilane.
The fluorine on fluorosulfone intermediates can also be displaced with other aryl or heteroaryl nucleophiles for form compounds of this invention. Examples of such nucleophiles include salts of phenols, thiophenols, xe2x80x94OH group containing aromatic heterocyclic compounds or xe2x80x94SH containing heteroaryl compounds.
Tautomers of such groups azo, hydrazo, xe2x80x94OH or xe2x80x94SH are specifically included as useful isomers. A preferred method of preparing intermediates in the synthesis of the substituted sulfones is by oxidation of an appropriate acetophenone, prepared from a flouroacetophenone, with for example, peroxymonosulfate, to form the corresponding phenol-ether. That phenol-ether is converted into its dimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride, followed by rearranging the dimethylthiocarbamoyl derivative with heat to provide the thiol required for preparation of the thioether intermediate.
Salts of the compounds or intermediates of this invention are prepared in the normal fashion wherein acidic compounds are reacted with bases such as those discussed above to produce metal or nitrogen containing cation salts. Basic compounds such as amines can be treated with an acid to for form the amine salt. A preferred amine salt is the hydrochloride salt formed by reaction of the free base with HCl or hydrochloric acid.
Compounds of the present can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent diastereoisomeric molecules, e.g., esters, amides, acetals, ketals, and the like, by reacting compounds of Formula I with an optically active acid in an activated form, a optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomericaly pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient because the compound can behave as a prodrug. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials.
In addition to the optical isomers or potentially optical isomers discussed above, other types of isomers are specifically intended to be included in this discussion and in this invention. Examples include cis isomers, trans isomers, E isomers, Z isomers, syn- isomers, anti- isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for delivery. 
Treatment Process
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
A contemplated compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is the similar use of a contemplated compound in the treatment of a disease state that can be affected by the activity of metalloproteases such as TNF-xcex1 convprtase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid. Exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl (C1-C6) halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C8-C20) halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme-inhibiting effective amount can be in amounts, for example, of about 0.001 to about 100 mg/kg body weight daily, preferably about 0.001 to about 30 mg/kg body weight daily and more usually about 0.01 to about 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Reminaton""s Pharmaceutical Sciences, Mack Publishing Co. (Easton, Pennsylvania: 1975) and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, (New York, N.Y.: 1980).
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.